Project Summary Increased use of genome-wide arrays and sequencing efforts have identified several single gene causes of autism spectrum disorder (ASD) and intellectual disability (ID), including SHANK3, known as Phelan-McDermid syndrome (PMS). Disruptions in SHANK3 pathways are also common to multiple monogenic forms of ID and ASD, such as tuberous sclerosis complex (TSC) and PTEN Hamartoma Tumor Syndrome (PHTS). PMS is characterized by severe global developmental delay/ID, motor skills deficits, delayed or absent speech, and ASD. Following a translational approach using Shank3 deficient model systems, specific deficits in synaptic function and plasticity in glutamate signaling have been documented. The proposed project represents a unique effort between clinical and basic science resources at five sites with recognized expertise in PMS and in ASD/ID: Icahn School of Medicine at Mount Sinai, Boston Children?s Hospital, Rush University Medical Center, Stanford University, and the National Institute of Mental Health. Specific aims are to: 1) comprehensively characterize the phenotype and natural history of PMS using a broad assessment battery; 2) identify biomarkers using electrophysiology; 3) develop a comprehensive clinical model of PMS to inform assessment and future clinical trials. This project is being undertaken in the context of a broader Developmental Synaptopathies Consortium (DSC) which uses a mechanistic approach to three rare genetic disorders with high penetrance of ASD/ID and aims to shed light on molecular pathways and targets relevant to ASD/ID: TSC, PHTS and PMS. Our DSC provides in-depth phenotyping and natural history characterization of patients with PMS. The current proposal seeks to extend our multi-site infrastructure to characterize an additional 100 patients across the lifespan. We will develop biomarkers and clinical outcome assessments (COAs) for clinical trials in PMS. We intend to show that specific neurophysiological biomarkers in PMS can be collected reliably across sites and will assess the relationship with clinically meaningful COAs. At the conclusion of this project, we expect to fully characterize the neurobehavioral phenotype of PMS and to track the natural history of the syndrome. Knowledge gained from this project will identify critical electrophysiological biomarkers and key assessment practices to provide a foundation for the development of novel therapies. Because the SHANK3 pathway is highly relevant to other forms of ASD/ID, knowledge gained from the proposed research will also improve our understanding of the neurobiology of developmental delay/ID and may aid in developing treatments of ASD/ID more broadly.